Pressurised metered dose inhaler comprising buffered pharmaceutical formulation

Abstract

To provide a formulation particularly useful for use in a pressurised metered dose inhaler for the treatment of respiratory diseases.SOLUTION: The present invention relates to an aerosol formulation comprising formoterol, beclomethasone dipropionate and glycopyrronium bromide, the formulation being contained in a coated can.SELECTED DRAWING: None

Description

Technical Field

[0001] The present invention generally relates to an aerosol formulation comprising at least a LABA, a LAMA, a corticosteroid and a propellant, which formulation is contained in a coated can and is particularly useful for use in a pressurized metered-dose inhaler for the respiratory tract region.

Background Art

[0002] A pressurized metered-dose inhaler (pMDI) is a well-known device for administering pharmaceuticals to the airway by inhalation. A pMDI device typically comprises a canister (or “can” as referred to herein, including for medical use) and an actuator housing having a mouthpiece. The can is usually crimped to a metering valve assembly. Depending on the active ingredient and additional ingredients such as additives, acids, the final pMDI formulation can be in the form of a solution or a suspension. A solution generally refers to one substantially free of precipitates or particles, and a suspension typically refers to a formulation containing undissolved matter or precipitates. A pMDI device can use a propellant to expel droplets containing the pharmaceutical as an aerosol into the airway. Over the years, the preferred propellants used in this regard have generally been chlorofluorocarbon derivatives commonly referred to as freons or CFCs, such as CCl3F (Freon 11 or CFC-11), CCl2F2 (Freon 12 or CFC-12), and CClF2-CClF2 (Freon 114 or CFC-114). Due to international concerns that fully or partially halogenated chlorofluorocarbons have critical values of the global warming potential (GWP) that affect the Earth's protective ozone layer, many countries have concluded the Montreal Protocol, which severely restricts their manufacture and use and should ultimately be completely phased out. As a result, hydrofluoroalkanes (HFAs), particularly 1,1,1,2-tetrafluoroethane (HFA134a) and 1,1,1,2,3,3,3-heptafluoropropane (HFA227a), have been identified and accepted as alternatives to CFCs in the pharmaceutical sector. Since then, the hydrofluoroalkane propellants HFA134a and HFA227a have been widely used in the respiratory field, particularly considering their effectiveness and compatibility with many active ingredients such as corticosteroids, long-acting beta-agonists (LABAs) or antimuscarinic drugs.

[0003] However, despite the effectiveness of the HFA propellant and its widespread application to many pharmaceuticals already on the market, alternative classes of propellants and alternative means for obtaining effective pMDI devices are constantly being investigated. As a general reference in this regard, see, for example, "Pharmaceutical Inhalation Aerosol Technology", Third Edition 2019, Anthony J. Hickey et Al, where on page 440, Table 18.3 compares several propellants potentially suitable for medical use in terms of their global warming potential.

[0004] This is also relevant to, for example, the optimization of mechanical elements of pMDI devices such as valves or cans, or the possibility of having spray devices, spray drying systems, or devices characterized by a more environmentally friendly impact that do not use propellants.

[0005] A further feature to consider when discussing pMDI devices is the apparent pH and water content of the formulation sprayed by the device. As general references in this regard, see, for example, WO01 / 89480 and WO03 / 074024.

[0006] Fluorocarbon polymers are commonly used for coating the inner surface of pMDI cans, for suspension formulations, to remove particle adhesion or deposition on the can walls, i.e., to avoid sticking, and to avoid the formation of by-products.

[0007] EP0820323 describes a pMDI in which part or all of the inner surface is coated with one or more fluorocarbon polymers for dispensing an inhalation drug formulation containing salmeterol and a fluorocarbon propellant, optionally in combination with one or more other pharmacologically active agents, wherein the inner surface of the can significantly reduces or essentially eliminates the problem of salmeterol adhesion or deposition.

[0008] WO2015 / 101576 describes a pMDI device that is particularly suitable for use with a solution of formoterol, beclomethasone propionate, and glycopyrronium bromide contained in an FEP-coated can. As disclosed therein, the formulation contained in the FEP-coated can has improved stability and a reduced amount of degradation products with respect to N-(3-bromo)-[2-hydroxy-5-[1-hydroxy-2-[1-(4-methoxyphenyl)propan-2-ylamino]ethyl]phenyl]formamide. Indeed, this product (identified as DP3) is a specific degradation product that results from the interaction of formoterol with bromide ions from glycopyrronium bromide when the two active ingredients are dissolved in an HFA ethanol-based system in the presence of an acid, particularly hydrochloric acid.

[0009] EP2706987 describes a formulation for use in a pMDI device, containing beclomethasone propionate and HFA152, which is particularly suitable for the treatment of respiratory diseases.

[0010] WO2018 / 051131 describes in Table 4 of Example 1 a pharmaceutical formulation containing beclomethasone propionate and formoterol fumarate dihydrate, a propellant containing 1,1-difluoroethane (HFA152a), optionally a LAMA drug such as glycopyrronium bromide, and glycerol. However, WO2018 / 051131 does not disclose a coating can suitable for use with the above formulation.

[0011] WO2018 / 051130 describes a pharmaceutical formulation comprising a drug component containing at least one pharmaceutically acceptable salt of glycopyrrolate and a propellant component containing HFA152a, wherein the formulation exhibits satisfactory stability without using an acid stabilizer.

[0012] WO2019236559, published on December 12, 2019, describes a pharmaceutical composition for use in a pMDI device, comprising beclomethasone propionate, formoterol fumarate dihydrate, glycopyrronium, a propellant selected from HFA134a, 227a and 152a, a co-solvent, an organic acid and optionally water.

[0013] US20160324778 describes a pharmaceutical composition for use in a pressurized pharmaceutical composition comprising a propellant selected from HFO-1234yf (2,3,3,3-tetrafluoropropene) and HFO-1234ze (1,3,3,3-tetrafluoropropene), and one or more active ingredients, such as formoterol and beclomethasone propionate, wherein the active ingredients are in the form of a suspension or solution with the propellant.

[0014] While the above prior art provides technical arrangements of effective formulations and devices, there is still a need to find a suitable pMDI device for use in the respiratory field, for example for the treatment of asthma and / or COPD, which not only aims to reduce the global warming potential (GWP), but also advantageously provides a good stabilization system, particularly with respect to the adjustment and maintenance of the apparent pH of the formulation contained in the device. In fact, it should be noted that the prior art does not mention an appropriate and practical method for buffering the apparent pH of formulations suitable for pMDI devices, which contain at least corticosteroids, LABA drugs, LAMA drugs and propellants. The apparent pH is actually an important parameter that can affect many aspects of pMDI formulations, especially when in solution form, such as the stability of LABA and / or LAMA drugs, shelf life, consistent delivery of drugs from the MDI into the aerosol, reproducibility of the final formulation, and maintenance of optimal chemical conditions within the can.

[0015] Surprisingly, it has been found that the apparent pH of a formulation suitable for a pMDI device containing at least corticosteroid, LABA, LAMA and a suitable HFA or HFO propellant can be stabilized by an internally coated canister with a dedicated metering valve system.

[0016] Surprisingly, it has been found that the use of an internally coated canister with a dedicated metering valve system can avoid the presence of a buffer and stably maintain the apparent pH of the pMDI formulation. In fact, the internally coated canister according to the present invention can stabilize the apparent pH even over a long period, as shown in the following experimental part of this specification. In this sense, the coated canister of the present invention can act as an apparent pH buffer system, and the use of a dedicated metering valve further increases the apparent pH buffering effect of the coated canister.

[0017] Advantageously, the coated canister of the present invention, comprising at least corticosteroid, LABA, LAMA and a suitable valve system containing a selected HFA or HFO propellant, can be readily used in a pDMI device for the treatment of respiratory diseases such as asthma and / or COPD, and also ensures good stability of chemical components over a long period, excellent aerosolization performance, and low GWP. SUMMARY OF THE INVENTION

[0018] In one aspect, the present invention relates to a can for use in a pMDI device, comprising a formulation comprising at least a corticosteroid, a LABA drug, a LAMA drug and an HFA152a or HFO propellant, said can being internally coated by a coating comprising a compound selected from at least an epoxy phenolic resin, a perfluorinated polymer, a perfluoroalkoxy alkane polymer, a perfluoroalkoxy alkylene polymer, a perfluoroalkylene polymer, a polytetrafluoroethylene polymer (Teflon), a fluorinated ethylene propylene polymer (FEP), a polyethersulfone polymer (PES), a fluorinated ethylene propylene polyethersulfone polymer (FEP-PES), a polyamide, a polyimide, a polyamideimide, a polyphenylene sulfide, a plasma, a mixture or combination thereof, said can being made of a material comprising at least one polymer selected from low density polyethylene, butyl rubber such as chlorobutyl or bromobutyl rubber, butadiene-acrylonitrile rubber, neoprene, EPDM (ethylene propylene diene monomer polymer), TPE (thermoplastic elastomer), cycloolefin copolymer (COC) or a combination thereof, and having at least one gasket and a valve. In a further aspect, the present invention relates to the coated can as described above, wherein the formulation comprising at least a corticosteroid, a LABA, a LAMA drug and an HFA or HFO propellant is preferably a solution further comprising an inorganic acid or an organic acid and / or a co-solvent.

[0019] In a further aspect, the present invention relates to a pMDI device for use in the respiratory field, particularly for the treatment of asthma and / or COPD, comprising the coated can as described above.

DETAILED DESCRIPTION OF THE INVENTION

[0020] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art.

[0021] The "molar ratio" between formoterol or a salt thereof or a solvate of the salt and an acid is calculated in consideration of the number of moles of formoterol or a salt thereof or a solvate of the salt in the formulation and the number of moles of the selected acid in the formulation.

[0022] Unless otherwise specified, the term "formoterol fumarate" or "FF" refers to (R,R)-(±) formoterol fumarate or its dihydrate.

[0023] Unless otherwise specified, the term "LABA" or "LABA drug" includes in its meaning long-acting β2 agonists known in the art.

[0024] Unless otherwise specified, the term "LAMA" or "LAMA drug" includes in its meaning long-acting muscarinic receptor antagonists known in the art.

[0025] The term "% w / w" means the weight percentage of a component relative to the total weight of the formulation.

[0026] The term "% w / v" means the weight percentage of a component relative to the total volume of the formulation.

[0027] A "stable" composition as defined herein means that the content of the remaining active ingredient at a given time point measured by HPLC / UV-VIS is at least about 90% w / w (weight percentage of the content relative to the initial content at time 0), preferably at least about 95% w / w, and the total content of degradation products is about 10% by weight or less, preferably about 5% by weight or less, relative to the initial content of the active ingredient at time 0.

[0028] Regarding the term "apparent pH" as contemplated herein, it should be noted that the calculation of pH is generally characteristic of an aqueous liquid where water is the main component, for example. In a relatively aprotic solvent such as an HFA-based system of the present invention, protons are not hydrated and their activity coefficients can be different from those in an aqueous solution. The Nernst equation for the electromagnetic field (EMF) (describing the potential of an electrochemical cell as a function of the concentration of ions involved in the reaction) is applied, and the glass electrode system of the pH meter generates a variable millivolt output according to the proton concentration and the polarity of the vehicle, and the reading of the pH meter represents the "apparent pH" according to the present invention. In this regard, the apparent pH according to the present invention can be measured by techniques known in the art, as shown, for example, in ""Correlation between Apparent pH and Acid or Base Concentration in ASTM Medium" Orest Popovych, Analytical Chemistry 1964, 36,4,878-882; Analytical Standard Test Method (ASTM) D6423 - 19 "Standard Test Method for Determination of pH of Denatured Fuel Ethanol and Ethanol Fuel Blends".

[0029] As described above, the present invention shows unexpectedly that when a coated can equipped with a dedicated valve system described in detail herein, suitable for a pMDI device, is used to contain a suitable formulation comprising at least a corticosteroid, a LABA drug, a LAMA drug and an HFA or HFO propellant, the apparent pH of such a formulation can be advantageously buffered between about 2.5 and 5, preferably between about 3 and 4.5, depending, for example, on the components of the formulation and / or their amounts, as described hereinafter. Having such a buffer system provides several advantages, such as an increase in the stability of the formulation over time, good shelf life, reproducibility of the final formulation, maintenance of optimal chemical conditions within the can, and consistent delivery of the drug from the MDI as an aerosol, especially with respect to the amount of formoterol.

[0030] In particular, by having a stable apparent pH with an internally coated can equipped with a dedicated valve system, the addition of an external conventional acid-base buffer system leading to more complex formulations can be avoided. By using the coated can together with a dedicated metering valve, it acts as an apparent pH buffer system, further increasing the stability of the formulation. In contrast, cans with an uncoated inner surface do not show the effect of maintaining a constant apparent pH over a long period for pMDI solution formulations, as shown in the following comparative examples.

[0031] Accordingly, in one embodiment, the present invention relates to a can equipped with a dedicated valve system for use in a pMDI device, comprising the formulation described herein and in the claims, wherein the apparent pH of the formulation is stabilized at a value of about 2.5 to 5, preferably about 3 to 4.5. In other words, the present invention also relates to a can described herein and in the claims suitable for buffering the apparent pH of a formulation comprising at least a corticosteroid, LABA, LAMA and an HFA or HFO propellant to about 2.5 to 5, preferably about 3 to 4.5.

[0032] The apparent pH of a pMDI formulation is affected by the formulation composition, for example with reference to the concentration of acid, etc., and the setting of an appropriate value can be achieved by selecting an appropriate amount and type of LABA, LAMA and / or corticosteroid drug, or by adding further components to the formulation as described hereinbelow.

[0033] For cans, coated cans known in the art can be suitably used in the present invention. Thus, the can can be made of metal, such as aluminum, or a metal alloy, stainless steel or anodized aluminum, fluorine passivated aluminum, etc. Alternatively, the can can be made of plastic or other suitable materials. Preferably, the can can be made of aluminum or stainless steel that is suitably coated and optionally anodized. The coating is typically applied to the inner surface of the can and thus provides an inner layer that functions as an interface between the inner surface of the can and the formulation contained in the can. Thereby, the inner surface coating prevents the adhesion of the components of the formulation to the can surface and also sets up a pH buffering system. Typically, the inner coating forms a coating layer characterized by having a thickness that meets the requirements of uniformity and homogeneity, as tested, for example, using a WACO enamel evaluation device available on the market. The inner coating covers at least 50%, preferably at least 95%, and even more preferably at least 99% of the inner surface of the can.

[0034] In this regard, suitable coated cans of the present invention preferably have a part or all of the inner surface coated with an inert organic or inorganic coating, including epoxy phenolic resin, perfluorinated polymer, perfluoroalkoxy alkane polymer, perfluoroalkoxy alkylene polymer (PFA), perfluoroalkylene polymer, polytetrafluoroethylene polymer (PTFE or Teflon), fluorinated ethylene propylene polymer (FEP), polyether sulfone polymer (PES), fluorinated ethylene propylene polyether sulfone polymer (FEP-PES), polyamide, polyimide, polyamideimide, polyphenylene sulfide, plasma, mixtures or combinations thereof.

[0035] By way of example, the term "FEP-coated" refers to a coating layer comprising FEP and any additional components, including additives, adhesives, aggregating agents, such as PES, isobutyl ketone.

[0036] The polymers listed above can be used in combination with further components or as part of a polymer mixture obtained, for example, by mixing two or more polymer compounds together. In this regard, the internal coating of the can according to the invention is intended to also include said mixture or combination. In one embodiment, the coated can of the invention is a can coated with FEP or PTFE, or more preferably a can coated with FEP-PES. In the case of an FEP-PES coating, since PES functions as an intermediate layer between the inner surface and the FEP polymer, a more uniform and homogeneous coating is ensured. In fact, it should be noted that, where appropriate, a plurality of coatings can be applied to the inner surface of the can to form a two-layer or multi-layer coating with improved homogeneity and stability.

[0037] In one embodiment of the invention, the can is an aluminum can characterized by having an inner surface coating containing an FEP-PES polymer. Aluminum FEP-coated cans suitable for the present invention are, for example, commercially available and in use on site.

[0038] As shown in the following experimental part of this specification, when a formulation in solution form, containing beclomethasone propionate (BDP), formoterol fumarate dihydrate, glycopyrronium bromide and HFA152a propellant, is contained in an FEP-coated can equipped with a dedicated valve system according to the invention, the apparent pH of the formulation is favorably maintained at the selected value even over a long period.

[0039] In one embodiment, the corticosteroid component of the formulation contained in the coating can according to the present invention is selected from the group consisting of budesonide, beclomethasone (BDP), such as the mono- or dipropionate ester, flunisolide, fluticasone, such as the propionate or furoate ester, ciclesonide, mometasone, such as the furoate ester, mometasone desonide, roflumilast, hydrocortisone, prednisone, prednisolone, methylprednisolone, naphrocort, deflazacort, halopredone acetate, fluocinonide acetonide, fluocinonide, clocortolone, tipredane, prednicarbate, alclometasone propionate, halometasone, rimexolone, deprodone propionate, triamcinolone, betamethasone, fludrocoritisone, desoxycorticosterone, roflumilast, etiprednol dicloacetate, and beclomethasone propionate (BDP) and budesonide are particularly preferred. In a further preferred embodiment, the corticosteroid component is beclomethasone propionate (BDP).

[0040] According to another embodiment, the amount of the corticosteroid component according to the present invention is included in the range of 0.01 to 0.7% w / w, more preferably 0.05 to 0.5% w / w, and even more preferably 0.1 to 0.3% w / w.

[0041] Regarding the LABA component of the formulation contained in the coating can according to the present invention, this is preferably selected from the group consisting of formoterol, formoterol fumarate, formoterol fumarate dihydrate, albuterol, carmoterol (TA-2005), indacaterol, milbeterol, bambuterol, clenbuterol, vilanterol, olodaterol, abediterol, terbutaline, salmeterol, diastereomer mixture, and pharmaceutically acceptable salts or hydrates thereof. In one embodiment, the LABA is formoterol fumarate, preferably formoterol fumarate dihydrate.

[0042] Alternatively, the formulation of the present invention may contain salbutamol, (R)-salbutamol (levalbuterol) and pharmaceutically acceptable salts or hydrates thereof.

[0043] Preferably, the amount of LABA according to the present invention is included in the range of 0.0005 to 0.04% w / w, more preferably 0.001 to 0.03% w / w, and even more preferably 0.005 to 0.02% w / w.

[0044] In one embodiment, the LAMA drug in the formulation contained in the coated can according to the present invention is selected from the group consisting of glycopyrronium, methscopolamine, ipratropium, oxitropium, trospium, tiotropium, aclidinium, and umeclidinium or pharmaceutically acceptable salts. In a preferred embodiment, the LAMA drug is glycopyrronium bromide. Preferably, the amount of the LAMA drug according to the present invention is included in the range of 0.001 to 0.08% (w / w), preferably 0.005 to 0.06% (w / w), and more preferably 0.01 to 0.04% (w / w).

[0045] The propellant of the formulation contained in the coated can according to the present invention is selected from HFA152a and hydrofluoroolefin (HFO).

[0046] In one embodiment, the HFO propellant of the formulation contained in the coated can according to the present invention is selected from the group consisting of 1,3,3,3-tetrafluoropropene (HFO-1234ze) and 2,3,3,3-tetrafluoropropene (HFO-1234yf). Preferably, the propellant is HFO-1234ze.

[0047] In a preferred embodiment, the propellant is HFA152a.

[0048] The formulation contained in the coated can according to the present invention can be in the form of a suspension or a solution. In one embodiment, the selected corticosteroid, LABA and LAMA components are preferably dissolved in the HFA or HFO propellant defined above, and thus provide a solution. Accordingly, in one particularly preferred embodiment, the present invention relates to an FEP coated can for use in a pMDI device containing a solution comprising at least beclomethasone propionate, formoterol fumarate dihydrate, glycopyrronium bromide and HFA152a.

[0049] As described above, in one embodiment, the formulation contained in the coated can according to the present invention may further contain additional components, such as additives, adjuncts, solvents, co-solvents, acids, low volatility components or further active ingredients, if desired. The addition of such components can be appropriately adjusted in accordance with the present invention, for example, to modulate the physicochemical properties of the formulation and / or to set an appropriate apparent pH that is desired to be maintained constant. In this regard, in one preferred embodiment, the present invention relates to a coated can for use in a pMDI device containing a formulation comprising a corticosteroid, a LABA drug, a LAMA drug, an HFA or HFO propellant, and optionally a co-solvent and / or an acid and / or a low volatility component.

[0050] Preferably, the co-solvent is a polar compound capable of increasing the solubility of the components in the formulation. Examples of suitable co-solvents are aliphatic alcohols having 1 to 4 carbon atoms, such as methanol, ethanol, propanol, isopropanol, etc., preferably ethanol, more preferably absolute ethanol.

[0051] When present, the co-solvent is used in an amount of 5% w / w to 20% w / w, more preferably 10% to 15%.

[0052] In one embodiment, the acid can be an inorganic acid or an organic acid, preferably selected from hydrochloric acid, hydrobromic acid, nitric acid, fumaric acid, phosphoric acid and citric acid, maleic acid, acetic acid, cinnamic acid, oxalic acid, lactic acid, 2-methylpropionic acid, malic acid, butanoic acid, tartaric acid, propionic acid, pentanoic acid, succinic acid, glycolic acid, hexanoic acid, malonic acid, glutaric acid, formic acid, adipic acid, ascorbic acid, benzoic acid, glucuronic acid or mixtures thereof, with hydrochloric acid being particularly preferred. According to a further preferred embodiment, the acid is concentrated or diluted, preferably 1M hydrochloric acid. Preferably, when the acid is 1M HCl, it is used in an amount contained in 0.001 to 0.08% w / w, preferably 0.005 to 0.06%, more preferably 0.01 to 0.04%.

[0053] Generally, the amount of acid selected is preferably chosen to have a final apparent pH of the solution contained in about 2.5 to 5, preferably 3 to 4.5 as described above. According to the present invention, by using a coated can equipped with a dedicated valve system, the selected apparent pH is maintained stable and substantially unchanged over time even when the pH is set by the presence of the acid, and thus, in the presence of an inorganic or organic acid, it solves the problem of how to control and stabilize the pH of a formulation suitable for pMDI application, including at least corticosteroids, LABA drugs and propellants.

[0054] In a further preferred embodiment, the pMDI solution of the present invention consists of or contains a LABA, a LAMA, and a corticosteroid dissolved in a system comprising HFA152a, 1M HCl, and EtOH. According to this further preferred embodiment, the LABA, the LAMA, and the corticosteroid are formoterol fumarate dihydrate, glycopyrronium bromide, and beclomethasone propionate, respectively.

[0055] As will be appreciated, these last-described embodiments are also intended to be included within the scope of the invention in any possible combination with all other preferred embodiments described above and below herein.

[0056] In one embodiment of the present invention, the molar ratio between the LABA and the acid, when present, is from 0.50 to 1.50, preferably from 0.9 to 1.1. In fact, it should be noted that within this range, the stability of the final formulation increases to a particularly convenient extent.

[0057] When present, the low volatility component has a vapor pressure of less than 0.1 kPa, preferably less than 0.05 kPa at 25°C, and is preferably selected from the group consisting of glycol, propylene glycol, polyethylene glycol, glycerol or their esters, ascorbyl palmitate, isopropyl myristate, etc., and isopropyl myristate and glycerol are particularly preferred.

[0058] According to one embodiment, the formulation of the present invention contains water in an amount of preferably less than 3000 ppm, more preferably less than 2000 ppm, and even more preferably less than 1500 ppm, based on the total weight of the formulation.

[0059] The present invention surprisingly solves the problem of how to effectively buffer the apparent pH of a commercial pMDI formulation containing corticosteroids, LABA drugs, LAMA drugs, and HFA or HFO propellants without additional components or substances that buffer but may nevertheless impair the stability and / or effectiveness of the formulation contained in the can. Also, from a manufacturing perspective, the present invention enables the production of immediately usable pMDI devices, including the coated cans described herein, using a simple and integrated manufacturing process. Further, by using a green propellant such as HFA152a, the present invention can not only solve the above problems but also address potential environmental problems resulting from the long-term use of other fluorinated propellants.

[0060] As shown above, the coated cans for use according to the invention are characterized by a dedicated metering valve system. In fact, surprisingly, the use of a specialized metering valve has been found to further increase the apparent pH buffering action of the coated cans according to the invention and is also beneficial with respect to residual formoterol, the overall stability and effectiveness of the formulation. Generally, the cans of pMDI devices are crimped to a metering valve for delivering a therapeutically effective dose of the active ingredient. The metering valve assembly includes at least a gasket seal. Preferably, the valve includes two or three gaskets made of the same or different materials. In this regard, according to the invention, the valve comprises two or three gaskets made of the same or different materials. Thus, according to the invention, at least one gasket is made of a suitable elastomeric material comprising at least one polymer selected from low density polyethylene, butyl, such as chlorobutyl or bromobutyl, butadiene-acrylonitrile, neoprene, EPDM (ethylene propylene diene monomer polymer), TPE (thermoplastic elastomer), cycloolefin copolymer (COC) or combinations thereof.

[0061] Preferably, the valve comprises three gaskets, and even more preferably, all of them are made of EPDM and are referred to herein as B-valves.

[0062] In a preferred embodiment, the valve comprises a gasket made of COC together with two gaskets made of EPDM and is referred to herein as A-valve.

[0063] In an equally preferred embodiment, the valve comprises two gaskets, preferably both made of chlorobutyl polymer, and is referred to herein as V-valve.

[0064] In a further preferred embodiment, the valve comprises a gasket made of butyl rubber together with two gaskets made of EPDM.

[0065] In yet another embodiment, the valve preferably comprises two gaskets made of bromobutyl, together with one gasket made of a material selected from the group consisting of chlorobutyl, butadiene-acrylonitrile, neoprene, EPDM (ethylene propylene diene monomer polymer), TPE (thermoplastic elastomer), cycloolefin copolymer (COC) or combinations thereof. Preferably, the valve comprises two gaskets made of bromobutyl, together with one gasket made of EPDM.

[0066] The metering valve according to the present invention can typically deliver an amount in the range of 25 to 150 μl, preferably in the range of 50 to 100 μl, and more preferably 50 μl or 70 μl per actuation. Valves suitable for the present invention are available on the market, for example from manufacturers well known in the art.

[0067] As a further advantage, it has surprisingly been found that, depending on the selected HFA propellant, the choice of valve can advantageously improve the effectiveness and reliability of the final pMDI device. For example, when using the HFA152a propellant in a coated can according to the present invention, an A-valve or a V-valve further improves the stability of the final formulation compared to a B-valve comprising, for example, three gaskets made of EPDM.

[0068] This improvement in stability is further enhanced when the formulation is in solution form, as shown in the experimental part of this application. In fact, the B-valve, when used in combination with the HFA152a propellant, can lead to leakage of the propellant, which can result in an undesirable loss of the product and can compromise the effectiveness of the pMDI device over time. Surprisingly, when the A-valve or V-valve is used in combination with the HFA152a propellant in the coated cans according to the invention, not only is the buffering effect of the apparent pH maximized, but leakage of the formulation is also substantially avoided. This results in an effective and convenient system that can be easily used in the final pMDI device. This versatility leads to a wide range of applications and customization possibilities for the final pMDI device containing the cans according to the invention, and thus to meet the various needs and requirements of patients and / or the market.

[0069] According to a preferred embodiment, the valve is selected from the A-valve and the V-valve, and the A-valve is even more preferred.

[0070] Thus, in a preferred embodiment, the invention relates to an FEP-coated can for use in a pMDI device, comprising a formulation comprising at least BDP, formoterol fumarate dihydrate, glycopyrronium bromide, HCl and an HFA152a propellant, wherein the FEP-coated can has a valve selected from the A-valve or the V-valve. According to this embodiment, the can further comprises ethanol, preferably anhydrous ethanol, if desired.

[0071] The coated can for use in a pMDI device according to the invention can be filled with the selected formulation by common methods used in the art. As a general example, the method comprises the following steps: a) preparing a solution comprising formoterol fumarate, BDP, glycopyrronium bromide and ethanol; b) filling the FEP-coated can with the solution; c) a step of adding HCl in an amount such that the molar ratio between formoterol fumarate dihydrate and the acid is 0.50 to 1.50; d) a step of adding 1,1-difluoroethane (HFA152a) propellant; e) a step of crimping onto an Aptar valve and gassing, and may include.

[0072] The pMDI containing the coated can according to the present invention may have the arrangement and configuration of a commonly used pMDI device, such as those already on the market as well-known formulations for treating, for example, asthma and / or COPD.

[0073] Unless otherwise stated, all of the above embodiments may be combined together and are intended to be regarded as part of the scope of the present invention.

[0074] Here, the present invention will be described by the following non-limiting examples.

Examples

[0075] (Experimental part) In the following Examples 1 and 2, the apparent pH was measured using a standard LiCl electrode commonly used for measuring pH in an organic medium. Since it is an MDI pressurized product, the following procedure was applied to measure the apparent pH of the formulation: 1. Cool the canister to at least -50 °C (immerse the canister in a dry ice bath or liquid nitrogen to lower the internal pressure to atmospheric pressure). 2. Cut the valve and open the canister to evaporate the propellant at room temperature. 3. Pour the remaining ethanol solution (containing the API) into a glass vial, make it up to a volume of 10 ml with anhydrous ethanol, and make it a volume sufficient for measurement with a standard LiCl electrode. 4. Measure the apparent pH of the reconstituted solution using a LiCl electrode.

[0076] Example 1 The aluminum FEP-coated cans according to the present invention were filled with a solution containing FF (0.011% w / w), BDP (0.18% w / w), glycopyrronium bromide (0.022% w / w), HCl 1M (0.02% w / w) and ethanol (12% w / w) in the presence of HFA152a.

[0077] The aluminum FEP-coated cans filled with the above solution and equipped with valve A, B or V were placed in a stability chamber at 25 °C and 60% R.H. (relative humidity).

[0078] The apparent pH (App pH) of the solution and the residual rate of formoterol fumarate dihydrate (FF% w / w) relative to the initial content were measured at T = 0, 1, 3 and 6 months, respectively.

[0079] The results are summarized in Table 1 below.

Table 1

[0080] Example 2 (comparative) Using uncoated cans equipped with valve A, B or V, the same analysis as in Example 1 was performed.

[0081] The apparent pH (App pH) of the solution according to Example 1 was measured at T = 0, 1, 3 and 6 months, respectively. The results are summarized in Table 2.

Table 2

[0082] As is clear from Tables 1 and 2 above, the use of FEP-coated cans filled with the solution according to the present invention in the presence of the HFA152a propellant with the indicated valves ensures a favorable stabilization of the pH of the solution contained therein even after a long period, for example 6 months, compared to T = 0.

[0083] In contrast, when using an uncoated can (comparison), even after storage for only one month at 25 °C, which can be regarded as room temperature, the pH may increase significantly with respect to the measured value at T = 0, and the FF% w / w may decrease.

Claims

1. 1. A canister for use in a pMDI device containing a formulation comprising at least a corticosteroid, a LABA drug, a LAMA drug and an HFA152a or HFO propellant, the canister being internally coated with a coating comprising a compound selected from at least an epoxy phenolic resin, a perfluorinated polymer, a perfluoroalkoxyalkane polymer, a perfluoroalkoxyalkylene polymer, a perfluoroalkylene polymer, a polytetrafluoroethylene polymer (Teflon), a fluorinated ethylene propylene polymer (FEP), a polyethersulfone polymer (PES), a fluorinated ethylene propylene polyethersulfone polymer (FEP-PES), a polyamide, a polyimide, a polyamideimide, a polyphenylene sulfide, a plasma, a mixture or combination thereof, the canister comprising a valve having at least one gasket made of a material comprising at least one polymer selected from low density polyethylene, butyl, such as chlorobutyl or bromobutyl, butadiene-acrylonitrile, neoprene, EPDM (polymer of ethylene propylene diene monomer), TPE (thermoplastic elastomer), cycloolefin copolymer (COC), or a combination thereof.

2. 2. The method of claim 1, wherein the corticosteroid is selected from the group consisting of budesonide, beclomethasone propionate, flunisolide, fluticasone, ciclesonide, mometasone, mometasone desonide, rofleponide, hydrocortisone, prednisone, prednisolone, methylprednisolone, naflocort, deflazacort, halopredone acetate, fluocinolone acetonide, fluocinonide, clocortolone, tipredane, prednicarbate, alclometasone propionate, halometasone, rimexolone, deprodone propionate, triamcinolone, betamethasone, fludrocortisone, desoxycorticosterone, rofleponide and etiprednol dicloacetate.

3. 3. The method of claim 2, wherein the corticosteroid is beclomethasone propionate or budesonide.

4. The can of any one of claims 1 to 3, wherein the LABA drug is selected from the group consisting of fenoterol, formoterol fumarate, formoterol fumarate dihydrate, arformoterol, carmoterol, indacaterol, mirveterol, bambuterol, clenbuterol, vilanterol, olodaterol, abesiterol, terbutaline and salmeterol.

5. 5. The method of claim 4, wherein the LABA drug is formoterol fumarate dihydrate.

6. 10. The can of claim 1, wherein the formulation alternatively comprises a drug selected from the group consisting of salbutamol and (R)-salbutamol.

7. The method of any one of claims 1 to 6, wherein the LAMA drug is selected from the group consisting of glycopyrronium, methscopolamine, ipratropium, oxitropium, trospium, tiotropium, aclidinium, and umeclidinium, or a pharma- ceutical acceptable salt.

8. 8. The method of claim 7, wherein the LAMA drug is glycopyrronium bromide.

9. A can according to any one of claims 1 to 8, wherein the HFO propellant is selected from the group consisting of 1,3,3,3-tetrafluoropropene (HFO-1234ze) and 2,3,3,3-tetrafluoropropene (HFO-1234yf).

10. A can according to any one of claims 1 to 9 which is internally coated with a coating comprising a fluorinated ethylene propylene (FEP) polymer.

11. A can according to any one of claims 1 to 10, containing a formulation further comprising one or more additives, co-solvents and acids.

12. The can according to claim 11, wherein the co-solvent is an aliphatic alcohol having 1 to 4 carbon atoms.

13. 13. The can according to claim 12, wherein the aliphatic alcohol is ethanol, preferably absolute ethanol.

14. 14. The can according to any one of claims 11 to 13, containing a formulation further comprising an inorganic or organic acid selected from the group consisting of hydrochloric acid, hydrobromic acid, nitric acid, fumaric acid, phosphoric acid, and citric acid, maleic acid, acetic acid, xinafoic acid, oxalic acid, lactic acid, 2-methylpropionic acid, malic acid, butanoic acid, tartaric acid, propionic acid, pentanoic acid, succinic acid, glycolic acid, hexanoic acid, malonic acid, glutaric acid, formic acid, adipic acid, ascorbic acid, benzoic acid and glucuronic acid.

15. 15. The can of claim 14, wherein the acid is hydrochloric acid.

16. 16. The can according to any one of claims 1 to 15, containing a formulation further comprising a low volatility component selected from the group consisting of glycol, propylene glycol, polyethylene glycol, glycerol or esters thereof, ascorbyl palmitate, isopropyl myristate.

17. A canister according to any one of claims 1 to 16, containing the formulation in the form of a solution.

18. Can according to any one of claims 1 to 17, wherein the valve is provided with three gaskets, all made of EPDM.

19. Can according to any one of the preceding claims, wherein the valve comprises a gasket made of COC together with two gaskets made of EPDM.

20. Can according to any one of claims 1 to 17, wherein the valve is provided with two gaskets, both made of chlorobutyl polymer.

21. Can according to any one of the preceding claims, wherein the valve comprises a gasket made of butyl rubber together with two gaskets made of EPDM.

22. 18. Can according to any one of claims 1 to 17, wherein the valve comprises two gaskets made of bromobutyl together with one gasket made of a material selected from the group consisting of chlorobutyl, butadiene-acrylonitrile, neoprene, EPDM (polymer of ethylene propylene diene monomer), TPE (thermoplastic elastomer), cycloolefin copolymer (COC) or combinations thereof.

23. Can according to any one of claims 1 to 22, wherein the propellant is HFA152a and the valve comprises a gasket made of COC together with two gaskets made of EPDM; or the valve comprises two gaskets, both made of chlorobutyl polymer.

24. A can according to any one of claims 1 to 23, containing a formulation having an apparent pH buffered between 2.5 and 5.

25. 25. A can according to claim 24, containing a formulation having an apparent pH buffered between 3 and 4.

5.

26. A pMDI device comprising a canister according to any one of claims 1 to 25.

27. 27. A pMDI device as claimed in claim 26 for the treatment of a respiratory disease selected from asthma and / or COPD.

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